Alcohol Use Disorders (AUDs) represent a major public health problem in the United States with over 8% of Americans meeting the DSM-IV criteria for an AUD. Excessive alcohol intake causes progressive neurodegeneration that often leads to cognitive and behavioral deficits, and subsequently alcoholism. To date, there are no approved therapies for alcohol-induced neurodegeneration, thus warranting investigation into novel mechanisms of neuroprotection. The endocannabinoid system has been implicated as a novel neuroprotective system in a variety brain injury models. Studies suggest that the endocannabinoid anandamide (AEA) is elevated after ischemic and traumatic brain injuries, which affords endogenous neuroprotection. However it is not know if AEA affords similar neuroprotection for alcohol-induced neurodegeneration. Therefore, the guiding hypothesis for this present proposal is that AEA tone is amplified by alcohol-induced brain damage as a neuroprotective mechanism and therefore potentiating AEA tone by inhibiting AEA degradation affords additional neuroprotection. Specific Aim 1 will utilize HPLC/MS/MS techniques to assess levels of AEA in the entorhinal/perirhinal cortex and hippocampus, two regions susceptible to alcohol-induced neurodegeneration in a binge model of an AUD. Additionally, immunoblotting will be used to elucidate the mechanism of altered AEA tone. Specific Aim 2 will utilize receptor autoradiography to assess cannabinoid 1 (CB1) receptor expression during a binge-alcohol exposure paradigm in the brain regions mentioned above. This will allow us to gain insight to the relationship between CB1 receptors and elevations of AEA in context of neuroprotection, as AEA may cause CB1 down-regulation. Aim 3 will consist of two experiments to evaluate the efficacy of enhancing AEA tone, by inhibiting fatty acid amide hydrolase (FAAH), to attenuate alcohol- induced neurodegeneration. Experiment 1 will determine an optimum dose of URB-595, a FAAH inhibitor, to attenuate alcohol-induced neurodegeneration in the entorhinal/perirhinal cortex and ventral dentate gyrus of the hippocampus using fluoro-jade b stain. The second experiment will test whether AEA neuroprotection is mediated through the CB1 receptor using the CB1 receptor antagonist SR-141716. These studies will provide important insight into the effects of binge alcohol administration on the endocannabinoid system as well as neuroprotective properties of the endocannabinoid system in alcohol-induced brain damage. These studies will lead to future investigation into the specific mechanisms linking the endocannabinoid system to alcohol- induced neurodegeneration. Additionally, these results will lead to novel approaches and/or novel pharmaceutical agents for the treatment of neurodegeneration linked to AUD's. PUBLIC HEALTH RELEVANCE: Current treatments for alcohol use disorders commonly referred to as alcoholism, although effective for some, are less than adequate. With over 8% percent of the population currently suffering from an alcohol use disorder, it is essential that new therapies become available for these individuals. The proposed studies will give insight into novel treatment strategies for the treatment of alcohol use disorders, specifically for the treatment of alcoholic brain damage.